Apoptosis plays an important role in atherogenesis. A positive correlation exists between the number of apoptotic cells in the plaque and plaque instability. Phagocytosis of apoptotic cells is relevant to progression of atherosclerosis towards the unstable phenotype. Impaired phagocytosis is associated with accelerated progression of the atherosclerotic plaque towards the unstable phenotype. Atherosclerosis, hence, can be treated with methods that enhance phagocytosis of apoptotic cells.
Apoptotic cells expose phosphatidylserine (PS) at their cell surface. Annexin A5 (anxA5) binds to PS expressed on the apoptotic cell surface. AnxA5 bound to the apoptotic cell inhibits its phagocytosis by shielding the PS, which PS is recognized by the phagocyte as an ‘eat me’ signal (Kenis et al. Exp. Cell Res. 312 (2006) 719-726; and references cited therein).
Asano et al. J. Exp. Med. 200(4), 459-467 (2004) show that a milk fat globule mutant containing a point mutation in its RGD motif, inhibits phagocytosis of apoptotic cells and induces production of auto-antibodies upon injection in mice.
Bérat et al., Biointerphases 2(4), 165-172 (2007) describe a rat annexin A5 variant wherein Thr-163 is replaced by Cys, and a synthetic oligopeptide containing the RGD (arginine-glycine-aspartate) motif and a Cys residue is coupled to the Cys residue of the annexin mutant through a disulfide bond. Matrices of these annexin-RGD conjugates were found to promote adhesion of human saphenous vein endothelial cells. The authors suggest that these results may open cell-transporting techniques and the like. The annexin variants in which the RGD motif is attached to a central part of the molecule via a Cys-Cys (disulfide) bridge may have the disadvantage of insufficient stability in various environments.